This issue features a deep dive into Medicaid managed care. 

Take a look at our fantastic June 2022 issue!

Healthcare providers should offer multiple sclerosis (MS) patients help for pain, fatigue, depression or anxiety at the time of diagnosis rather than waiting, according to two new studies.

Clinically significant levels of pain, fatigue and depression, and anxiety were commonly seen in newly diagnosed patients, according to Kevin Alschuler, Ph.D., principal investigator and director of psychology service at the University of Washington Medicine’s Multiple Sclerosis Center, writing in 

In their study, Alschuler and colleagues had newly diagnosed adults with MS/clinically isolated syndrome self-report measures of pain, fatigue, depression, and anxiety at one, two, three, six, nine, and 12 months after MS diagnosis. (Clinically isolated syndrome refers to the first episode of what may represent the onset of MS.)

They found that 60% of the patients experienced fatigue; 50% had pain, 47% went through depression, and 39% lived through anxiety within the first year of diagnosis.

“The take home was that we found these symptoms — pain, fatigue, depression and anxiety — quite prevalent” at the point of diagnosis, Alschuler said in a 

. “We want to address this immediately, rather than five or 10 years down the road,” he said.

 followed the same cohort of 230 patients through the first year after their diagnosis.

Alschuler was also the lead author of this study. He and the research team examined the quality of life for patients immediately after, at two months, three months, six months, nine months and then one year after diagnosis.

They found that, on average, quality of life was high and stable.

“Patients who are newly diagnosed have to deal with the emotional impact of the diagnosis, as well as numerous tests and treatment decision-making,” Aschuler said. If the patients were “doing great” at diagnosis, they had a tendency to stay that way throughout the first year, Alschuler noted. “If they were struggling, they also tended to stay that way,” he added.

The stability in quality of life suggests that patients can be assessed early after diagnosis for key variables that are predictive of both current and future quality of life, the researchers noted.

Both Alschuler and Dawn Ehde, Ph.D., a clinical psychologist in the UW School of Medicine's Department of Rehabilitation Medicine and co-author of the 

 study, are interested in early non-pharmaceutical interventions for common symptoms experienced by MS patients.

“Through symptom self-management, including cognitive behavioral therapy, we help patients become empowered with coping skills, especially in the areas of fatigue and pain,” Ehde said. “We teach them how to use strategies such as relaxation or mindfulness meditation techniques, as well as how to pace themselves to decrease fatigue and better manage stress.”

Patients who learn these skills often find that not only do their pain and fatigue lessen, they are able to do more of what is important to them despite their MS, Ehde said.

The next step for the research team is to explore options for early interventions to help newly diagnosed patients.

Articles


Screening for depression also should happen quickly to maintain quality of life, two new studies of multiple sclerosis indicate. 


Studies Find MS Patients Need Early Help for Pain and Anxiety

The COVID-19 pandemic created profound challenges for organizations as they adapted to serve customers and keep their businesses running amid a global health crisis that triggered shutdowns, closures and quarantines.

Virtually overnight, organizations of every type had to reinvent how workers did their jobs and how customers received goods, services, and support. Whether due to choice or necessity, some businesses set up employees to do their jobs remotely. Other organizations, particularly those whose workers were considered essential, had to change processes and procedures to ensure the safety of employees and customers as they came into physical contact with people in offices, stores, and other public venues.

Many organizations also faced another employee-related dilemma: a mass exodus that soon would be labeled The Great Resignation — which is now shifting to The Great Reshuffle and even The Great Retention — also causing further disruptions. A March 2022 

article reported that 47 million Americans voluntarily quit their jobs in 2021. The 

 report analyzed 10-plus years of labor data that suggests the 2021 Great Resignation was a response to 2020 when far fewer employees quit their jobs likely due to the uncertainty of the pandemic.

For human resources executives, The Great Resignation…The Great Reshuffle…The Great Retention – however you might wish to refer to it – along with the pandemic have prompted a reevaluation of their hiring, training, retention and employee communications policies. 

Modivcare has been no different. What follows is a summary of the specific employee-related challenges the company faced during the pandemic and the lessons learned. We believe these lessons are important to remember not just during times of sudden and drastic change, but every day.

During a time of crisis, it’s easy to lose sight of your organization’s fundamental purpose. Things may be moving so fast that you’re in survival mode. In the case of Modivcare, the purpose of our business is to help members “make connections to care.”

For our members, transportation or personal care in the home were not optional during the pandemic. If you were on dialysis, you had to get to the dialysis center. And because what our employees do makes them essential workers, Dan Greenleaf, our CEO, decided we were going to keep our offices and care centers open to ensure we could address the needs of our members, which were acute. Dan didn’t want to run the risk of service disruptions when members were so dependent on us for transportation and home care.

Starting at the beginning of this year, Modivcare transitioned to a model that allows for some people – including operational leaders and care center agents – to work from home (WFH). Our turnover numbers, which declined during the height of the pandemic, have continued to fall since we went to a partial WFH model, even in the care center. In contrast, according to a recent report, attrition rates for care centers that provide customer care and support have exceeded 87% since the start of the COVID-19 pandemic, more than double the historical agent attrition rate of 30%-40%.

We’ve had success in retaining employees by providing the WFH option. Most importantly, though, we think our employees identify with our purpose and recognize what we do for our members is critical. They’ve stayed focused on our purpose. We have visual reminders of our purpose all around our offices. For example, thanks to a partnership we have with Access Gallery, artists with disabilities have designed pieces that embody Modivcare’s purpose, vision, and services for underserved communities that are installed in our offices in Denver.

The Great Reshuffle has caused many organizations to rethink their relationships with employees. In many cases, this has led to workers being offered more flexible work hours and conditions, as well as other benefits designed to improve job satisfaction. These are both positive developments and things we have done at Modivcare.

But we also have learned that it is important for an organization to protect its right to set expectations for employees. These might be as straightforward as requiring employees to be vaccinated or establishing a code of behavior in the workplace. While these types of expectations may drive away some employees who prefer more latitude, organizations involved in healthcare should and must hold workers to a high standard, even during a disruptive event. They have an obligation, after all, to meet the needs of people who are counting on them for life-or-death services.

Though it’s always important for organizations to communicate frequently and transparently with employees, this need becomes even more urgent during a pandemic or any type of disruptive event. 

When circumstances are changing rapidly – as happened on an almost daily basis in the early months of 2020 – employees not only are anxious, but they also eagerly seek information and assurance. If organizations don’t position themselves to their employees as trusted sources of information, many workers will turn instead to news feeds and social media for guidance and direction.

By frequently communicating a clear and consistent viewpoint during periods of uncertainty, organizations can serve as an informational “North Star” to employees. This can both allay the concerns of workers and allow them to provide useful information to other people in their lives (such as family members and friends outside the workplace) who also may be impacted by whatever changes are underway. Providing employees with a steady flow of reliable information can ease anxiety in employees and the affected people in their lives because they aren’t left to wonder what’s happening.

The pandemic has had a permanent impact on the workplace, yet organizations still are in catch-up mode as they try to adapt strategically and operationally. To thrive going forward, organizations must figure out how to 1) build and maintain a strong culture in an increasingly remote workplace, and 2) implement effective recruitment and retention strategies in an economy where there are fewer workers. 

A strong focus on purpose, a clear set of expectations, and being a trusted source of information for employees will go a long way toward helping organizations achieve these goals.

, a technology-enabled healthcare services company headquartered in Denver. 

To thrive organizations must figure out how to build and maintain a strong culture in an increasingly remote workplace, and implement effective recruitment and retention strategies in an economy where there are fewer workers.

  Managing and Retaining Employees During Periods of Disruptive Change

Researchers have identified what they say is a critical lack of communication about biosimilars between patients with breast cancer and their oncologists, based on 

They also said many switches from the reference product Herceptin (trastuzumab) are dictated by payers and much needs to be done to improve the levels of trust between payers, patients, and oncologists if biosimilar acceptance is to grow.

“There is a need for tailored and effective patient and oncologist information and education on trastuzumab biosimilars, along with improved health care communications regarding switching,” wrote lead author 

, Ph.D., M.S., an assistant professor in the Department of Biomedical and Health Information Sciences at the University of Illinois at Chicago. 

Papautsky and her colleagues reported their results in May in the journal 

In two separate surveys, Papautsky and her colleagues collected responses from 143 patients with breast cancer and 33 medical oncologists. The researchers said that 63.9% of patients reported they had been switched to a trastuzumab biosimilar--most often Kanjinti (69.8%)--and of those, 40.8% reported they had been given no prior notice they would be switched.

In none of the responses did oncologists ever say that the switch to a biosimilar was initiated by them. It was most commonly the case that the switch was mandated by the payer (45.2%). Oncologists were much more likely than patients to report satisfaction with the way biosimilar information had been communicated.

“The discrepancy between patient-reported experiences and oncologists’ perceptions of the patient experience suggests a lack of adequate information that may be a challenge not only to the uptake of trastuzumab biosimilars, but to the patient oncologist relationship,” Papautsky and her fellow researchers wrote.

The authors expressed strong concern that these communication gaps be rectified because, they said, Herceptin is a costly drug and biosimilars represent an important opportunity to improve patient access and lower the cost of health care. Payers have latched onto the savings aspect, they said. “Literature suggests that with increasing availability of biosimilars, a variety of switching scenarios have become common across disease types.”

They cautioned that “with guidelines often being vague, the practice of switching is largely unregulated.”

Because of the above-described patient/doctor disconnect on biosimilars, many patients resorted to self-directed research to find out about these biologic alternatives, the report said.

Among patients participating in the survey, 58.1% were fully covered by private insurance and 99.3% and 91.4% were female and white, respectively. Responding oncologists were most likely to work in an urban setting (68.0%) or at an academic center or affiliate (35.3%).

Despite the communication problems, most patients (55.2%) said they were given an option to switch to a Herceptin biosimilar--it wasn’t forced on them. And of patients who responded, 63.9% went through with the switch. Papautsky said 8.6% declined to switch.

However, lack of prior notification about switching was a problem, patients reported (40.8%); and just 26.4% said their treating oncologist or physician briefed them beforehand about biosimilars. Smaller percentages of patients said they got that type of information instead from advanced practice practitioners (5.7%), chemotherapy nurses (15.5%), or others.

Oncologists said that if not dictated by payers, switching decisions were typically initiated by pharmacies (29.0%) or hospital/treatment center administrations (19.4%).

The three most common reasons for switching, as reported by oncologists, were payer requirements (23.5%), biosimilars were considered identical to Herceptin (14.1%), and hospitals wanted to save money (12.9%).

Few patients or oncologists felt that the payers could be trusted to make the right decisions about switching (9.3% vs 12.1%, respectively). Patients were less likely than oncologists to agree they had been given the opportunity to ask questions about biosimilars (35.3% vs 58.8%) or that the biosimilar would be as effective in treating the cancer (43.4% vs 79.4%).

If biosimilar acceptance is to grow, it’s going to take a great deal of work to improve the levels of trust between payers, patients, and oncologists.

Researchers Identify a Communications Breakdown Over Herceptin Biosimilars

Researchers have discovered a specific combination immunotherapy that shows promise in treating patients with liver cancer.

The therapy involves a tumor-suppressing lipid molecule — nanoliposome C6-ceramide (LipC6) — and an antibody for cytotoxic T-lymphocyte antigen 4 (CTLA4). When used together, the two slowed tumor growth and enhanced the strength of tumor-attacking T cells, the University of Missouri, Columbia, said in a 

The FDA has approved one antibody that targets CTLA4. Bristol Myers Squibb’s Yervoy (ipilimumab) is available as both a monotherapy and in combination to treat a variety of cancers, including melanoma, renal cell carcinoma, colorectal cancer, non-small-cell lung cancer, and esophageal cancer.

Photo credit: Justin Kelley/University of Missouri Health Care

“Our analysis revealed the combination therapy significantly extended the life span of tumor-bearing mice compared with the mice with a single type of therapy or no therapy at all,” said co-principal investigator Guangfu Li, Ph.D., DVM, associate professor in the Department of Surgery and Department of Molecular Microbiology and Immunology at MU.

Li and colleagues published the research in the journal 

Federation of American Societies of Experimental Biology (FASEB)

Li said the findings are especially promising given the current lack of effective therapies to treat patients with liver cancer, the third-leading cause of cancer-related deaths in the United States. For patients diagnosed with liver cancer, the average five-year survival rate of all stages is 20%, according to the American Cancer Society.

 talked with Li about the combo treatment and its commercial application.

 What is the significance of this research?

 What is particularly notable is that we have now demonstrated that LipC6 treatment significantly improves the ability of anti-CTLA-4 antibodies to suppress liver cancer. Anti-CTLA4 antibody in combination with anti-PD-1/PD-L1 antibody was approved by the FDA to use in human patients with liver cancer; LipC6 as monotherapy was also approved by the FDA to use in human clinical trials for solid tumors including liver cancer.

In our study, we have demonstrated the therapeutic effect of their combination in a mouse liver-cancer model. Thus, their combination could be quickly approved by the FDA for the human clinical trial. We are now working together with our collaborators on the application of clinical trials of this combinational therapy in human patients with liver cancer.

 What is involved in bringing the treatment to market?

 We have submitted a patent application for this combinational treatment against cancer.

Staveley O-Carroll, M.D., Ph.D., professor in the Department of Surgery at MU and Mark Kester, Ph.D., director of the nanoSTAR Institute and a professor in the Department of Pharmacology, Biomedical Engineering, Molecular Physiology & Biophysics at the University of Virginia, and I have worked closely together since we were colleagues at Penn State College of Medicine.

Our initial high-impact paper showing these ceramide nanoliposomal particles were effective against hepatocellular cancer was published in 

 in 2012. We subsequently have combined this technology with immunotherapy in work that was funded by a multi-PI R01 from the National Cancer Institute and featured in 

The three of us have patented the combination of this technology with immunotherapy and now, more specifically, CTLA4 therapy.

 has been founded to produce GMP-grade quality nanoliposomal particles. After the recent completion of a successful phase 1 trial in solid tumors that showed that Ceraxa as a monotherapy surpassed all pharmacokinetic endpoints, we are now well-positioned to move to phase 2 studies.

Based on our provocative and powerful data, we are working with Pendreabio to open a phase 2 trial combining Ceraxa with anti CTLA4 therapy for liver cancer. We are also submitting an academic/industry partnership grant to the National Institutes of Health to fund this clinical trial, in addition to a VA Merit Award to fund a similar trial for our veterans.

 Have other similar studies been conducted on the combination treatment, or is this groundbreaking research?

 To my knowledge, no other similar studies have been conducted.


A study in mice has found that a combination immunotherapy slowed tumor growth and activated anti-tumor immune response.


Researchers Identify Possible Liver Cancer Immunotherapy

Keith Loria is a contributing writer to Medical Economics.

One of the worries about COVID-19 vaccination was whether people living with HIV would respond as well to the vaccine as people without HIV.


But so far, most of the evidence has allayed those concerns, including results reported by a group of Canadian researchers.

, Ph.D., a professor at Simon Fraser University in British Columbia, Canada, and her colleagues reported that people living with HIV had the same or an even stronger antibody response to a third shot of a vaccine and that was especially so for those who were vaccinated with the Moderna vaccine.

Brumme and her coinvestigators reported results as a preprint in medRxiv in March.

The study was based on a comparison between 99 people living with HIV with 152 people without HIV.

Brumme noted, though ,that the people living with HIV and control groups were not perfectly matched in terms of age, sex and other characteristics, but the study was large enough so that the research team could account for these differences in the analyses.

“This study was important to do because we knew that COVID-19 vaccination was particularly important for people living with HIV, as previous research had suggested that this group may be at increased risk of severe COVID-19,” Brumme said. “But, at the time, there was very little data on COVID-19 vaccine immune responses in this population.”

Furthermore, Brumme noted, impaired responses to COVID-19 vaccination had been seen in certain immunocompromised groups. Also, there was previous evidence from other types of vaccinations — flu shots, for example — that the immune system response to vaccination might be less robust in people living with HIV, even those who antiretroviral therapy.

Eighty-two of the people living with HIV in the study received two doses of mRNA vaccine, eight received the two doses of the 

 — which has not been approved by the FDA — and eight were vaccinated with one dose of the Oxford-AstraZeneca vaccine and one of two mRNA vaccines. Of the 80 people who received a third shot, 23 were boosted with the Pfizer vaccine and 56 with the Moderna one.

The research team measured antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement and viral neutralization against wild-type and omicron strains up to six months following two-dose vaccination, and one month following the third dose in the entire

“Though humoral responses naturally decline following two-dose vaccination, we found no evidence of lower antibody concentrations nor faster rates of antibody decline in PLWH (people living with HIV) compared to controls after accounting for sociodemographic, health and vaccine-related factors,” the research team noted. “We also found no evidence of poorer viral neutralization in PLWH after two doses, nor evidence that a low nadir CD4+ T-cell count compromised responses.”

The researchers discovered no difference in the rate of decline of antibodies after the second dose between people with HIV and the control group, plus after a third dose, antibody levels had risen above the concentrations observed one month after the second dose and in almost half of cases, concentrations were above the upper limit of the antibody assay.

“The main takeaway was that people with HIV, who have well-controlled viral loads on therapy and preserved CD4+ T-cell counts, mount strong and functional antibody responses to two and three-dose COVID-19 vaccination, including to the omicron variant that is now dominant,” Brumme said. “In fact, after controlling for sociodemographic, health- and vaccine-related variables, the vaccine responses observed in people with HIV were comparable to people without HIV.”

Those who had received two doses of the Oxford Astra-Zeneca vaccine, older people and people with multiple health conditions were found to more likely experience lower antibody levels as well.

The researchers concluded that PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after two- and three-dose COVID-19 vaccination, thought the results underscore the immune benefits of third doses in light of omicron.

The findings suggest that having a previous history of low CD4 count will not compromise vaccine responses. Additionally, those with well-treated HIV have just as good, if not better, responses to a third vaccine dose than people without HIV.

Results may help allay some of the concern that COVID-19 vaccination might not be effective among those living with HIV.

People Living With HIV and on Retroviral Therapy Have Strong Response to COVID-19 Vaccination: Canadian Study

Although there have been two previous known cases of HIV remission involving stem cell transplant in men, researchers have reported the first-ever case of a woman going into remissions went following a transplant.

, M.D., chief of pediatric infectious diseases at the David Geffen School of Medicine at UCLA and UCLA Mattel Children’s Hospital, and 

, M.D., of Johns Hopkins University, led a research team as part of the 

International Maternal Pediatric Adolescent AIDS Clinical Trial Network

 (IMPAACT) that studied a woman with HIV who received a cord blood stem cell transplant to treat acute myeloid leukemia. 

 earlier this year at the Conference on Retroviruses and Opportunistic Infections. The study showed that the woman has displayed no detectable levels of HIV for 14 months despite cessation of antiretroviral therapy (ART).

The woman had been on antiretroviral for four years at the time of her acute myeloid leukemia diagnosis and achieved acute myeloid leukemia remission after chemotherapy.

In 2017, the woman received a transplant of CCR5Δ32/Δ32 cord blood stem cells supplemented with adult donor cells from a relative. Once receiving the transplant, she engrafted with 100% cord blood cells at day 100 and had no detectable HIV. By 37 months post-transplant, she ceased ART.

It was pointed out by the researchers that prior to her receiving the stem cell transplant, the woman’s HIV was well controlled but detectable. The study team also noted that there were no traces of HIV in the participant for 14 months, aside for a transient detection of trace levels of HIV DNA in the woman’s blood cells at 14 weeks after stopping ART.

“This study provides hope for the use of cord blood cells or a combination of cord blood cells and haploidentical grafts to achieve HIV-1 remission for individuals requiring transplantation for other diseases,” Bryson said in a statement. “It also provides proof that HIV-1 viral ‘reservoirs’ can be cleared sufficiently to afford remission and possibly cure in the setting of resistant target cells.”

Although the CCR5Δ32/Δ32 mutation is rare, cord blood banks may provide a previously untapped resource, according to the researchers, and the combination therapy would enable clinicians to take advantage of the unique benefits offered by each type of graft for more diverse populations.

The previous two incidents of HIV remission resulting from a stem cell transplant occurred in a 

, who was known as the Berlin patient, who was in HIV remission for 12 years and deemed cured of HIV when he died of leukemia in 

, and a Latino male who was in HIV remission for more than 30 months.

The third case of HIV remission suggests that CCR5Δ32/Δ32 cord stem cell transplantation should be considered to achieve HIV remission and cure for people living with HIV who require such a transplant for other diseases, Bryson said.

Woman received cord blood stem cell transplant as a treatment for acute myeloid leukemia. No detectable levels of HIV were found for 14 months after cessation of antiretroviral therapy.

First Known Case of HIV Remission for Woman After Stem Cell Transplant

 its approval for the cancer medicine Ukoniq (umbralisib). Ukoniq was approved to treat two specific types of lymphoma: marginal zone lymphoma and follicular lymphoma. The agency is advising healthcare professionals to stop prescribing Ukoniq and switch patients to alternative treatments.

This is happening in the wake of the increased scrutiny over accelerated approvals. Last year, FDA’s re-evaluation of previous accelerated approvals saw nine indications either withdrawn or revoked.

Updated findings from TG Therapeutics’ UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq for the treatment of patients with chronic lymphocytic leukemia. As a result, regulators determined the risks of treatment with Ukoniq outweigh its benefits.

 a partial clinical hold on Ukoniq for chronic lymphocytic leukemia and non-Hodgkin lymphoma. Although the trial met its endpoint progression-free survival, a first analysis of overall survival showed a hazard ration of 1.23. An overall survival hazard ratio above 1.00 implies potential risk that the investigational therapy is causing harm. But based on the ad hoc nature of the analysis, about 15% of patients had missing or outdated survival data. And when excluding deaths related to COVID-19, the hazard ration was 1.04.

FDA approves Kymriah for adults with follicular lymphoma.

 for Novartis’ Kymriah (tisagenlecleucel) for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. Kymriah is now FDA approved in three indications and is the only chimeric antigen receptor (CAR)-T cell therapy approved in both adult and pediatric indications.

Follicular lymphoma is the second most common form of non-Hodgkin lymphoma, representing about 22% of non-Hodgkin lymphoma cases. It is often an unrelenting malignancy with a relapsing and remitting pattern, and patients may be exposed to a median of five lines of prior treatment. The efficacy of these regimens drops off rapidly in later lines of treatment.

Kymriah is also approved to treat children and young adults with B-cell acute lymphocytic leukemia and adults with relapsed or refractory large B-cell lymphoma.

FDA approves two Opdivo regimens for metastatic esophageal cancer.

 both Opdivo (nivolumab) in combination with chemotherapy and in combination with Yervoy (ipilimumab) as a first-line treatment for adult patients with advanced or metastatic esophageal squamous cell carcinoma.

Both Opdivo and Yervoy were developed by Bristol Myers Squibb. The new combinations, including Opdivo with fluoropyrimidine- and platinum-containing chemotherapy, are approved for patients regardless of PD-L1 status.

The approvals are based on the phase 3 CheckMate-648 trial, which evaluated Opdivo in combination with chemotherapy and Opdivo plus Yervoy each compared with chemotherapy alone.

Opdivo is approved both as a monotherapy and in combination with chemotherapy and Yervoy for five indications in upper gastroesophageal cancers.

FDA approves Evrysdi in pre-symptomatic newborns with SMA.

 a label extension for Evrysdi (risdiplam) to include babies under two months old with spinal muscular atrophy (SMA). The approval is based on interim efficacy and safety data from the RAINBOWFISH study in newborns, which showed that the majority of pre-symptomatic babies treated with Evrysdi achieved key milestones such as sitting and standing with half walking after 12 months of treatment.

Evrysdi is now approved to treat SMA in children and adults of all ages. Genentech leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics.

 the review timeline of the new drug application for Amylyx Pharmaceuticals’ AMX0035 (sodium phenylbutyrate/taurursodiol) for the treatment of patients with amyotrophic lateral sclerosis (ALS). The updated Prescription Drug User Fee Act (PDUFA) goal date is Sept. 29, 2022 (formerly June 29, 2022).

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord.

The FDA has extended review time to allow for review of additional analyses of data from the company’s clinical studies. This move follows an advisory committee meeting in March 2022 in which six of the 10 members voted no on the question of whether the open-label extension of the phase 2 CENTAUR trial established a conclusion that AMX0035 is effective in the treatment of patients with ALS.

FDA issues refusal to file letter for pegzilarginase.

 a Refusal to File (RTF) letter for Aeglea BioTherapeutics’ biologics license application (BLA) for pegzilarginase for the treatment of arginase 1 deficiency (ARG1-D).

The FDA has requested additional data to support effectiveness, such as evidence showing that plasma arginine and metabolite reduction predicts clinical benefit in patients with ARG1-D or clinical data demonstrating a treatment effect on clinically meaningful outcomes. The FDA also requested additional information relating to chemistry manufacturing and controls.

The BLA was submitted in April 2022 and was based on positive results from Aeglea’s double-blind, placebo-controlled PEACE phase 3 study and its ongoing long-term extension study, as well as a phase 1/2 clinical trial and its open-label extension study.

The FDA has put a clinical hold on a trial to support the Rx-to-OTC switch for Cialis (tadalafil) because of an issue related to the protocol design. Sanofi’s Actual Use Trial (AUT) has not yet recruited any patients.

The Actual Use Trial design uses a real-world setting to assess the ability of consumers to use a product in an over-the-counter setting according to the proposed product labeling. This is key in applications for switching medications to nonprescription use.

 that it continues to work with the FDA to move the Cialis program forward. Lilly, which developed Cialis, signed an agreement with Sanofi in 2014 for the nonprescription development of Cialis.

FDA accepts Dupixent application for treating skin lesions.

 for priority review the supplemental biologics license application (sBLA) for Dupixent (dupilumab) to treat adults with prurigo nodularis, a chronic inflammatory skin disease that causes extreme itch and skin lesions. The target action date for the FDA decision is September 30, 2022.

Dupixent is a human monoclonal antibody that inhibits the signaling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways and is not an immunosuppressant. It is being developed jointly by Sanofi and Regeneron.

The sBLA is supported by data from two pivotal phase 3 trials evaluating the efficacy and safety of Dupixent in patients 18 years and older with uncontrolled prurigo nodularis. Both trials met the primary and key secondary endpoints, showing Dupixent significantly improved disease signs and symptoms compared with placebo, including reduction in itch and skin lesions.

Dupixent is approved for use in certain patients with atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis and eosinophilic esophagitis in different age populations. Its most recent approval in May 2022 was to treat patients with eosinophilic esophagitis, an inflammatory condition that causes the esophagus to narrow and makes it difficult to eat.

The FDA has withdrawn the approval of Ukoniq, which is used to treat two specific types of lymphoma. In approvals, the regulatory agency has approved a new indication for Kymriah, two addition Opdivo regimens, and extended the use of Evrysdi in newborns with SMA. The agency also accepted for review Dupixent to treat skin lesions but extended the review of a new ALS therapy, refused to file an application for a rare metabolic disorder, and put a hold on the trial for Cialis OTC.

FDA Updates for Week of May 31

Riabni (rituximab) is a biosimilar to Rituxan that has been on the U.S. market for 18 months. It has achieved an average sales price (ASP) discount of 20% off the reference product. A new review 

makes the case for using this product across all indications of the originator based on pharmacologic and clinical comparative studies. The paper was funded partly by Amgen, which makes Riabni, and the corresponding author, Vladimir Hanes, an Amgen medical director until recently.

Riabni is the most recent of three Rituxan biosimilars the FDA has approved--the others being Truxima (2018) and Ruxience (2019). Riabni is approved in the United States for all oncologic indications of Rituxan, but not rheumatoid arthritis (RA), although Rituxan is.

Rituxan attacks the blood cells that are responsible for the inflammation in RA, but this process is so different from the drug’s efficacy in oncology that Amgen sought to justify “extrapolation” to use in RA by doing comparative studies of Riabni in RA as well as oncology (non-Hodgkin lymphoma, NHL).

“Although the approval of a candidate biosimilar may be extrapolated to indications that share a mechanism of action, this was more challenging for (Riabni) because (Rituxan) is indicated for a broad range of oncological and autoimmune diseases,” wrote lead author Patrick Cobb, M.D., of St. Vincent Cancer Center in Billings, Montana, and his colleagues.

“In addition to differences in disease pathology, RA and non-Hodgkin lymphoma patient populations are quite distinct and expected to have different comorbidities and co-medications.”

Comparative clinical efficacy and safety trials for Riabni and Rituxan were performed in patients with NHL and RA. 

“The totality of evidence supported the conclusion that Riabni is highly similar to Rituxan and provided scientific justification for extrapolation to other approved indications of Rituxan,” Cobb wrote. Rituxan is also indicated for chronic lymphocytic leukemia, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.

To obtain regulatory approval, developers of biosimilars must demonstrate that their products have no clinically meaningful differences from the reference products. Clinical equivalence in RA for Riabni and Rituxan was demonstrated in a large, 57 center study in the European Union and United States. The primary end point was the change from baseline in Disease Activity Score 28 for RA with C-reactive protein. This test measures the severity of RA conditions including joint tenderness and swelling.

At week 24, the mean decrease from baseline was -2.197 and -2.125 for Riabni and Rituxan, respectively, which investigators said were comparable to findings from other trials of Rituxan in patients with RA.

In the JASMINE trial, Riabni and Rituxan were compared in patients with follicular lymphoma, a type of NHL. The primary end point was overall response rate. The findings also pointed to equivalence between the two brands. Investigators said 78.0% and 70.2% of Riabni and Rituxan patients, respectively, had a complete, partial, or unconfirmed complete response. “Overall, there were no clinically meaningful differences in efficacy or safety of Riabni compared with Rituxan in patients with follicular lymphoma,” Cobb wrote.

The totality of evidence considered in this analysis included a comparative analytical and functional similarity assessment, which reveals whether the critical qualities of the reference product match those of the biosimilar. “As evidenced by results from cell-based assays and binding studies, Riabni and Rituxan were similar in their biological and functional properties,” Cobb wrote.

Clinical pharmacokinetic and pharmacodynamic studies also demonstrated similarity.

In their conclusions, the authors expressed confidence that the growth of biosimilar use would be supported by a payer emphasis on cost reduction. Riabni, Truxima, and Ruxience were aimed at a roughly $6.5 billion global market for Rituxan (2019 sales), and ASP discounts for Ruxience and Truxima reached 33% and 36%, respectively, by the second quarter of 2021, according to Amgen.

Rituxan global sales were about $2.7 billion in 2021, down 38% from the year before, an indication of formidable biosimilar competition.

The review, partly funded by Amgen, the maker of Riabni, makes the case for using the biosimilar to Rituxan for all indications of the originator.

Review Paper Argues for Broader Use of Riabni, a Rituxan Biosimilar

Anal cancer incidence rates have been increasing for years in the United States and people living with HIV are at an increased risk of developing anal cancer.

 titled “Impact of HIV on Anal Squamous Cell Carcinoma Rates in the United States, 2001-2015” that was published in the 

 examined the trend,  and the researchers shared some ideas about what might be done about it.

“In prior analyses, we showed that during 1980-2005 in the U.S., 28% of anal cancers among men and 1% of anal cancers among women occurred among people with HIV,” said study author 

, Ph.D., M.H.S., a senior investigator in the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. “We sought to extend this analysis to 2001-2015 and estimate the fraction of the general population anal squamous cell carcinomas, the major histologic subtype of anal cancer, that occurred among people living with HIV in the U.S.”

The researchers also sought to understand how anal squamous cell carcinomas (SCCs) among people with HIV have influenced trends over time in anal SCC incidence rates.

Data was obtained from a linkage of HIV and cancer registries in a dozen U.S. regions. The

proportion of anal SCCs occurring among people living with HIV was estimated by sex, age group and race and ethnicity. 

The National Cancer Institute’s HIV/AIDS Cancer Match Study is the world’s largest study of cancer among people living with HIV and 44 % of individuals living with HIV in the U.S. reside in the regions included in the study, Shiels said. “This study is ideal because it includes a large number of people living with HIV and also includes general population cancer registry data for comparison.”


The findings showed that during 2001-2015, for men, 32.5% of anal SCCs occurred in people with HIV, while for women, 3% occurred in people with HIV. The fraction of anal SCCs among people with HIV was greatest in the 20-49 age group and in Black and Hispanic individuals. Shiels noted the disproportionate burden of HIV among Black and Hispanic individuals in the U.S. and that it is likely attributable to socio-ecological factors that influence HIV prevention and treatment outcomes.

“Among men, but not women, increases in rates of anal SCC between 2001-2009, followed by a nonsignificant downward trend, were strongly influenced by anal SCCs among people with HIV,” Shiels said. “Public health measures aimed at preventing anal SCCs among people living with HIV could substantially reduce anal SCCs in the U.S. population.”

Though anal cancer is rare in the general population, it is a leading cancer site among people with HIV. Therefore, the research team stressed that more research focused on the prevention, early detection and treatment of anal cancer is needed in this population.

“It is important to note that human papilloma virus (HPV) vaccination protects against anal cancer, and more research is needed to understand the effectiveness of HPV vaccination among people living with HIV,” Shiels said.

Study shows that among men, about one-third of squamous cell carcinoma anal cancers are among people living with HIV.

  People Living With HIV at Increased Risk for Anal Cancer: NCI Study

Chief nuring officer, Stanford's Children Hospital

As nursing makes up the largest portion of the healthcare workforce, it is important to foster an environment where nurses and nursing leaders are put in a position to positively impact the future of health care and steer the industry’s evolution to holistic care models, where it moves beyond treating a condition.

As we enter year three of the pandemic, we’ve seen the definition of holistic care be tested, challenged, and also enhance this method of caring, ultimately improving the quality of patient care.

It is during these times that healthcare organizations must support the workforce striving for nursing excellence, especially during turbulent times to allow them to perform at their best at the point of care.

Regardless of the field of healthcare, both patients and the workforce are dealing with many new psychosocial elements that impact their well-being. The pandemic has brought on many personal and professional stresses that contribute to periods of emotional exhaustion, anxiety, depression and other mental health concerns.

Care goes beyond the “healing” or “fixing” of an injury or ailment.It extends well into “treatment” in which providers must be able to offer emotional and mental care as well.

Mental health remains an area that has been heavily impacted during the pandemic, and it has put a severe strain on resources. There is value in aligning both the clinician and operations side of healthcare to create the right environment for nurses.

To achieve this, organizations can build an inclusive environment where staff feel that they can bring their full selves to work for the betterment of patients and families. Examples include holding focus groups to connect and share experiences and welcoming open conversations around tough challenges that people are facing.

Creating a healthy environment for both patients and staff is of the utmost importance. Organizations must encourage anyone in need to explore the mental health and wellness resources available at their institution.

At Stanford Children’s Health, we make it practice that if you see someone who is struggling, check in with them, offer support and let them know you care. With the right environment, staff are supportive of each other’s needs and feel comfortable offering a helping hand.

Ongoing education and workplace development

As the healthcare environment changes, so must our approach to learning and development. Hospitals and health care systems must focus on all care elements, from building resilience to supporting well-being to communicating during trauma. As an industry, we need to continue to provide resources for leaders and staff to develop stronger skills to meet new demand.

In March, Stanford Children’s Health brought in a national speaker to discuss ways that we could address these concerns for our patients, and how conversations change when we focus on resilience and overall wellbeing (for both the patient and ourselves).

This nontraditional form of development led to engaged conversation and actionable steps that could be brought to the bedside. Investing this time in guiding the next generation of nurse leaders is one way to drive meaningful progression.